Cannabinoid receptor subtypes CB1 (brain) and CB2 (spleen) constitute a category of the important GPCRs drug targets. CB receptors have been implicated in pain transduction and perception as well as neuroinflammation and autoimmune disorders. Finn et al., Current Neuropharmacology 2004, 2(1):75-89; and Walter et al., British Journal of Pharmacology 2004, 141(5): 775-85. In fact, natural marijuana-derived cannabinoids have been used to relieve pain for millennia. Research publications have demonstrated the analgesic, anti-hyperalgesic and anti-inflammatory actions of selective CB 1 receptor agonists. Howlett et al., Neuropharmacology 2004, 47(Suppl. 1): 345-58. Activation of CB1 receptors results, however, in sedation and undesirable psychotropic effects. Efforts have been made to design CB2 ligands that selectively agonize CB2 receptors to treat chronic pain and neuronal disorder diseases without the undesirable effects associated with activation of CB1 receptors in the brain. Malan et al., Current Opinion in Pharmacology 2003, 3(1): 62-67.
The CB2 receptor was initially cloned from macrophages and was found to exist predominantly in peripheral areas of the body enriched with B-lymphocytes (e.g., in spleen and lymph nodes). Munro et al., Nature (London) 1993, 365(64411): 61-65. The level of CB2 expression in various types of inflammatory cells and immune competent cells is 10-100 times higher than CB1 receptor in these cell types. Galiegue et al., Eur J Biochem 1995, 232(1): 54-61; and Carlisle et al., International Immunopharmacology 2002, 2(1): 69-82. Cannabinoids exhibit immunosuppressive properties by interfering with humoral immunity, cell-mediated immunity, and cellular defenses against infectious agents. Berdyshev Chemistry and Physics of Lipids 2000, 108(1-2): 169-90. Overall, the emerging literature reveals the important roles of the CB2 system and CB2 ligands on immune modulation.
Therapeutic potential of CB ligands has been shown in multiple reviews. Whiteside et al., Current Medicinal Chemistry 2007, 14(8): 917-36; Huffman J. W., Mini-Reviews in Medicinal Chemistry 2005, 5(7): 641-49; Pertwee R. G., Pharmacology & Therapeutics 2002, 95(2): 165-74; Hall et al., Lancet Oncology 2005, 6(1): 35-42; Howlett et al., Neuropharmacology 2004, 47(Suppl. 1): 345-58; and Carter et al., Physical Medicine and Rehabilitation Clinics of North America 2004, 15(4): 943-54, ix. Although CB2 selective compounds have been limited in the clinic, the cannabinoids could potentially be useful in treating autoimmune and immunological disorders (e.g. multiple sclerosis). They have also been studied as anti-inflammatory agents that alleviate inflammatory pain, Mbvundula et al., Inflammopharmacology 2004, 12(2): 99-114; Malan et al., Current Opinion in Pharmacology 2003, 3(1): 62-67; and Cravatt et al., Journal of Neurobiology 2004, 61(1): 149-60, as anti-cancer agents that inhibit the growth of tumors of immune origin as well as glioma tumors and non-melanoma skin cancers, McKallip et al., Blood 2002, 100(2): 627-34, and as agents to induce apoptosis in immune system cancer. Bifulco et al., Recenti Progressi In Medicina 2003, 94(5):194-98.
It is apparent that the CB2 receptor has a complex involvement involved with the immune system, with tumor cells, and with inflammation. The discovery of CB2 receptors in the CNS contrasts with previous efforts to detect non-CB1 receptors in brain tissue. Van Sickle et al., Science 2005, 310(5746): 329-32. The purpose of these receptors beyond immune cell regulation remains controversial. Still, these studies did open the possibility of non-psychotropic therapeutic interventions, using enhanced endocannabinoid levels localized in the brain, and they offer therapeutic promise for treating central nervous system disorders. Whiteside et al., Current Medicinal Chemistry 2007, 14(8): 917-36.
In summary, available evidence suggests that cannabinoids could be valuable, particularly as adjuvants for symptom control in a range of conditions for which standard drugs are not fully satisfactory. Ashton Addict. Biol. 1999, 4(2): 111-26. Work has been limited, however, in relation to the design of CB2 ligands that do not confer psychotropic side effects. The slow pace of development in this regard has been due largely to a lack of information about the three-dimensional structures of the CB receptors and ligand binding sites.
Accordingly, need exists for CB2 chemical probes that can be used to distinguish the CB1 and CB2 pharmacophore features for structure-based design, and to identify novel CB2 selective ligands with the potential for development into therapeutic agents that have no psychotropic side effects.